Abstract

To identify novel genomic regions that regulate sex determination, we utilize the powerful C57BL/6J-YPOS (B6-YPOS) model of XY sex reversal where mice with autosomes from the B6 strain and a Y-chromosome from a wild-derived strain, Mus domesticus poschiavinus (YPOS), show complete sex reversal. In B6-YPOS, the presence of a 55-Megabase (Mb) congenic region on chromosome 11 protects from B6-YPOS sex reversal in a dose dependent manner. Using mouse genetics backcross designs and high-density single nucleotide polymorphism (SNP) arrays, we narrowed the congenic region to a 1.5 Mb genomic on chromosome 11 that confers 80% protection from B6-YPOS sex reversal when one copy is present and complete protection when two copies are present. It was previously believed that the protective congenic region originated from the 129S1/SviMJ (129) strain. However, genomic analysis revealed that this region is not derived from 129 and most likely is derived from the semi-inbred strain POSA. We show that the small 1.62 Mb congenic region is located within the Sox9 promoter protects against B6-YPOS sex reversal and promotes the expression of Sox9, thereby driving testis development within the B6-YPOS background. Through 30 years of backcrossing, this congenic region was maintained, as it promoted male sex determination and fertility despite the female-promoting B6-YPOS genetic background. Our findings demonstrate that long-range enhancer regions are critical to developmental processes and can be used to identify the complex interplay between genome variants, epigenetics, and developmental gene regulation.

The Genetics Society of America (GSA), founded in 1931, is the professional membership organization for scientific researchers and educators in the field of genetics. Our members work to advance knowledge in the basic mechanisms of inheritance, from the molecular to the population level.